Renal lithiasis, or kidney stones, and associated complications are a major burden on our health care system affecting 8.8% of the population in the United States. Oxalate is a simple organic acid widely consumed by humans and is also a constituent in 80% of all kidney stones. Many adults host intestinal oxalate-degrading bacteria, which can degrade oxalate and significantly reduce the amount circulating in the blood. Individuals who do not host oxalate-degrading bacteria can acquire them and the benefits they confer, as probiotic supplements. However, these probiotics are often lost in the intestines over time, and a high oxalate diet is required for their maintenance. The mechanisms driving the loss of probiotic oxalate-degrading bacteria on a low oxalate diet represents a considerable gap in our understanding of the gut microbiome and is a challenge for the successful treatment of hyperoxaluria. My long-term goal is to understand the mechanisms that facilitate the persistent colonization of bacteria in the gut and develop effective probiotics to treat oxalate-related illnes. The overall objectives of this application are to use molecular techniques such as metagenomics and qPCR to identify the mechanisms behind the loss of oxalate-degrading bacteria inoculated into a host. We hypothesize that the oxalate-degrading function is supported by the metabolic activity of the non- degrading proportion of the gut microbiota. Three specific aims are proposed to test this hypothesis: (1) Determine the persistence of the oxalate-degrading community on variable oxalate loads; (2) Identify the unique metabolic pathways and microbial taxa that are present in persistent oxalate-degrading microbiota; and (3) Quantify the differences in the relative expression of genes encoding for oxalate-sensitive anion-transport proteins in animals with or without natural communities of oxalate-degrading bacteria. Completion of the specific aims will identify the mechanisms facilitating the persistence and loss of oxalate-degrading communities in the gut. Outcomes will have a positive impact by identifying the molecular mechanisms that lead to the persistence and loss of oxalate-degrading bacteria, which is an important step in making oxalate-degrading bacteria a viable treatment for hyperoxaluria.